IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism

被引：240

作者：

Grassian, Alexandra R. ^{[1
]}

Parker, Seth J. ^{[4
]}

Davidson, Shawn M. ^{[3
]}

Divakaruni, Ajit S. ^{[5
]}

Green, Courtney R. ^{[4
]}

Zhang, Xiamei ^{[1
]}

Slocum, Kelly L. ^{[1
]}

Pu, Minying ^{[1
]}

Lin, Fallon ^{[1
]}

Vickers, Chad ^{[1
]}

Joud-Caldwell, Carol ^{[1
]}

Chung, Franklin ^{[1
]}

Yin, Hong ^{[1
]}

Handly, Erika D. ^{[4
]}

Straub, Christopher ^{[1
]}

Growney, Joseph D. ^{[1
]}

Vander Heiden, Matthew G. ^{[2
,3
]}

Murphy, Anne N. ^{[5
]}

Pagliarini, Raymond ^{[1
]}

Metallo, Christian M. ^{[4
,6
]}

机构：

[1] Novartis Inst Biomed Res, Cambridge, MA USA

[2] Koch Inst Canc Res, Cambridge, MA USA

[3] MIT, Cambridge, MA 02139 USA

[4] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

来源：

CANCER RESEARCH | 2014年 / 74卷 / 12期

关键词：

REDUCTIVE GLUTAMINE-METABOLISM; ISOCITRATE DEHYDROGENASE MUTATIONS; ELECTRON-TRANSPORT CHAIN; MUTANT IDH1; ALPHA-KETOGLUTARATE; IN-VIVO; ONCOMETABOLITE; 2-HYDROXYGLUTARATE; GLUCOSE-OXIDATION; GLIOMA-CELLS; GROWTH;

D O I：

10.1158/0008-5472.CAN-14-0772-T

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed C-13 metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation.

引用

页码：3317 / 3331

页数：15

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